1. The role of autophosphorylation in mediating erbB-2-specific signal transduction was analyzed. Results indicate the tyrosine- phosphorylated COOH-terminal of the erbB-2 moiety, influence substrate binding (and henceforth their phosphorylation) by increasing the affinity of erbB-2 for its intracellular substrates. A model was proposed for the role of the phosphorylated COOH- terminus as a stabilizer of the receptor substrate(s) multimolecular complex. 2. Studies on the inhibition of erbB-2-induced transformed phenotype were undertaken with monoclonal antibodies (MAbs) directed against the erbB-2 extracellular domain. Several classes of MAbs were identified which acted as positive or negative modulators of erbB-2 action. In particular, one MAb (#23) was able to cause dramatic reduction of tumorigenic growth in nude mice of NIH/3T3 cells transformed by erbB-2 or human tumor cells with erbB- 2 amplification. 3. Based on our previous results, characterization and isolation of novel substrates for the epidermal growth factor receptor (EGFR) was performed. We have at present identified and cloned genes for seven new proteins which are phosphorylated on tyrosine by an active EGFR kinase.